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Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB

Author

Listed:
  • Donato D’Angelo

    (University of Padua)

  • Víctor H. Sánchez-Vázquez

    (Thomas Jefferson University)

  • Benjamín Cartes-Saavedra

    (Thomas Jefferson University)

  • Denis Vecellio Reane

    (Helmholtz Zentrum Munich)

  • Ryan R. Cupo

    (Perelman School of Medicine at the University of Pennsylvania
    Perelman School of Medicine at the University of Pennsylvania)

  • Hilda Delgado de la Herran

    (Helmholtz Zentrum Munich)

  • Giorgia Ghirardo

    (University of Padua)

  • James Shorter

    (Perelman School of Medicine at the University of Pennsylvania
    Perelman School of Medicine at the University of Pennsylvania
    Perelman School of Medicine at the University of Pennsylvania)

  • Ron A. Wevers

    (Radboud University Medical Centre)

  • Saskia B. Wortmann

    (Salzburger Landesklinken (SALK) and Paracelsus Medical University
    Radboudumc)

  • Fabiana Perocchi

    (Helmholtz Zentrum Munich
    Technical University of Munich
    Munich Cluster for Systems Neurology)

  • Rosario Rizzuto

    (University of Padua
    National Center on Gene Therapy and RNA-Based Drugs)

  • Anna Raffaello

    (University of Padua
    University of Padua)

  • György Hajnóczky

    (Thomas Jefferson University)

Abstract

Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. Additionally, OPA1 decreases, and aggregation occurs, accompanied by mitochondrial fragmentation. Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes. Thus, mtCU and fusion activity are dependent on CLPB, and their impairments might contribute to the disease caused by CLPB variants.

Suggested Citation

  • Donato D’Angelo & Víctor H. Sánchez-Vázquez & Benjamín Cartes-Saavedra & Denis Vecellio Reane & Ryan R. Cupo & Hilda Delgado de la Herran & Giorgia Ghirardo & James Shorter & Ron A. Wevers & Saskia B., 2025. "Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57641-9
    DOI: 10.1038/s41467-025-57641-9
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